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Understanding Autism, Neurochemically and Beyond

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Rates of Autism Spectrum Disorder (ASD) are rising in the U.S., and as a result, scientists are scrambling to figure out what is behind this increase and what we should do about it. A neurological disorder that varies widely in presentation and severity, Autism is broadly defined by the CDC as a disability “that can cause significant social, communication and behavioral challenges.” Since the 1990’s, autism prevalence has shifted from 1 in 150 children to 1 in 69. This may be caused by changes in diagnostic practices, such as the inclusion of Asperger’s into the Autism spectrum and looser diagnostic criteria, but a variety of other factors have been proposed as well.

Neurochemically, there are many proposed mechanisms that lead to the development of ASD. One of the most prominent hypotheses of pathophysiology involves abnormal neuroconnectivity, where neurons are overconnected within local circuits but underconnected across brain regions further apart, possibly due to an initial misplacement and impaired removal of unneccesary neurons during development. An imbalance of glutamate and GABA may also be involved, resulting in a net overexcitation of certain brain areas that would help explain the repetitive behaviors, seizures, sensory processing difficulties and social impairments commonly seen in Autism. Genetics, environmental factors and neuroinflammation, along with  components, are additional aspects of autism development that have been demonstrated through research.

People with Autism often experience life differently from neurotypical individuals, but to what degree does this warrant treatment or interventions? A fairly convincing argument has even been made by some that the occurrence of ASD within a population provides evolutionary benefits, with common autistic qualities such as enhanced memory and heightened perception contributing to the specialization of roles that further society. However, I have worked with several dozen teens and adults with Autism at a therapeutic recreation program, many of whom on the more severe end of the spectrum are unable to independently care for themselves or communicate verbally. Especially without the right type of support system, challenges like these can make it difficult to connect with others.

I am by no means an expert on ASD treatment, but my view is this: we should help individuals with ASD foster skills that will directly improve their quality of life, such as communicating their needs and thoughts they want to express to others. However, we should spend just as much energy toward creating an environment where they feel free to be authentically themselves. This is both by helping those around them learn how to best support their needs, but also by teaching society to accept and integrate individuals with ASD into their community. 

When it comes down to actual treatment decisions, things can get tricky. Do therapies such as Applied Behavior Analysis (ABA) help children with Autism “overcome” their symptoms? Or are there aspects of ABA that force children with Autism to assimilate to societal expectations in ways they may not need to? Different medications/therapies may pose similar ethical dilemmas. Given the wide range of symptom presentation and severity, it may be best to have a variety of treatment routes and options as well. I don’t have the answers to questions like these, but I hope that someday we will. In the meantime, we each play a part in creating a world where anyone can thrive.

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Medical Marijuana Decreases Drug Abuse

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The endocannabinoid system is a naturally occurring system within the brain. Researchers have been looking at CBD and THC, which can both be extracted from cannabis, as therapeutics. CBD and THC are chemically similar to the body’s endogenous (natural) endocannabinoids. Research has shown promising results, so doctors have been starting to prescribe medical marijuana to patients instead of alternative drugs. So how has this impacted drug abuse?

From: http://mjnewsnetwork.com/legal/medical-marijuana/medical-marijuana-id-card-applications-top-2000/

In The Brain

First, it is important to understand the endocannabinoid system (ECS) in the brain. The ECS has retrograde signaling and involves several receptors and ligands. Two of the major endogenous endocannabinoids (eCB) are Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG). Also, the CB1 and CB2 receptors are the most prevalent receptors in this system. Both receptors are G-protein coupled receptors (GPCRs). This means that when a ligand binds, G-proteins are activated.

Activated CB1 and CB2 receptors result in a signaling cascade that releases neurotransmitters from the postsynaptic neuron which travels back to the presynaptic neuron. These signals then modulate the presynaptic neuron’s signaling, effecting all signaling done by the presynaptic neuron. The two major endocannabinoids, along with exogenous cannabinoids CBD and THC, bind to the cannabinoid 1 (CB1) receptor. The CB1 receptor is located on presynaptic neurons and mediates the central nervous system’s (CNS) effects. AEA and 2-AG activate the CB1 receptor, which regulates adenylate cyclase activity and inhibits cAMP, voltage-gated potassium channels, calcium channels, and neurotransmitter release.

Next is the cannabinoid 2 (CB2) receptor. The CB2 receptor is mainly found on microglia and is involved with the immune system, including inflammation. AEA and 2-AG are agonists for the cannabinoid receptors and are triggered by an influx of calcium at postsynaptic sites after synaptic activity. Overall, the eCB system mediates a variety of events including synaptic plasticity, learning and memory, pain perception, neuroprotection, inflammation and mood.

Artstract created by H.Pfau

Medical Marijuana and Drug Abuse

As medical marijuana is becoming legal, doctors are switching to marijuana or CBD as a therapeutic in replacement of other medications. This is significantly decreasing the amount of addictions and overdoses for several reasons. First, the majority of people who get addicted to opiates were once prescribed them. So, instead of prescribing opiates for pain management, doctors are prescribing medical marijuana or CBD. Second, people who are already addicted to opiates are willingly switching to marijuana, therefore reducing the amount of addictions and overdoses. Same goes for anxiety prescriptions. Since marijuana and CBD have been shown to reduce anxiety, people are using it as a therapeutic instead of other medication that pertain to anxiety, such as Xanax. Further, showing a third way medical marijuana is reducing drug abuse. Lastly, marijuana has been shown to induce a “forgetting effect” by stimulating the part of the brain that controls memory. This can be helpful for people who are struggling with addiction by reducing cravings and reducing the memory related to drug use. Potentially, resulting in a fourth way medical marijuana is reducing drug abuse. 

 

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Using the Gut to Treat Depression through Endocannabinoids

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Your brain controls everything in your body right? Well, somewhat. In the case of some reflexes, the signal to pull your hand back from something hot may not have actually traveled to your brain until you’ve already completed the motion. On another level, there is evidence that the gut may also function somewhat independently, and actually communicate much more with the brain than previously thought. In some ways we already know this is true. When you’re standing in line for a roller coaster, you might feel a little nervous, and your stomach starts to turn. This is your brain and gut communicating, and this talk is a two way street. Both affect each other heavily, which can be positive or negative, depending on the situation. 

If the gut microbiome is disturbed (reasons can include stress, low fiber, sleep disturbances, etc.), this appears to not be great for our overall health. These disturbances typically lead to a low grade, local inflammation of the gut, which then turns systemic. Because of the gut-brain connection, systemic inflammation becomes neuroinflammation, or inflammation of the brain’s tissue. This can have all kinds of adverse effects that can show themselves behaviorally, or change the way the brain functions. Since the gut can affect the brain negatively like this, there are also positives that can occur. One of the major upsides that research is looking into is that we may be able to address and treat issues that are commonly associated with the brain, such as anxiety and depression, through the gut.

When the gut is inflamed, it has been found that endocannabinoid signalling is lower than it should be (and yes, endocannabinoids relate to cannabis). It makes sense then that restoring proper levels of endocannabinoids would help to treat inflammation. Using neuroinflammation as an example, restoring this endocannabinoid signalling to the gut relieves neuroinflammation as well, helping to make the entire body work more smoothly. As talked about in my obesity blog post (shameless plug), inflammation can perpetuate and worsen obesity, which can increase insulin resistance, which, as talked about in my Alzheimer’s post, can lead to neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s. Basically, inflammation is really not great, and can cause a cascade of negative effects that can happen over a period of decades. The good news though, is that inflammation can be treated using endocannabinoids, but that also doesn’t mean we shouldn’t try to prevent inflammation in the first place. 

Something interesting that has been found in this gut-brain link is the ability for the gut to moderate pain and how we perceive it. Chronic pain that doesn’t have a reason to be painful (as in there isn’t any reason for pain to occur), also called neuropathic pain, is a common thing among Americans. Endocannabinoids moderate this pain, and so if someone is struggling with chronic pain of this sort, increasing their endocannabinoid levels can help alleviate pain (along with inflammation that can go along with the pain!).

With all this being said, it’s important to do what your grandma probably told you, eat well, do things you like to do, and sleep well and often, and your endocannabinoid levels and gut will thank you for it. Ok, she might not have said that last part, but I bet she was thinking it.

 

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The Endocannabinoid System’s Role in Therapeutics

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artstract by C. Eisenschenk

When the endocannabinoid system is mentioned, most people generally infer that it has something to do with cannabis, more commonly known as marijuana. What most don’t realize is that the endocannabinoid system is a natural occurring system within the body and has cannabinoid receptors to bind with endogenous ligands (endocannabinoids (eCB)). This system plays a prominent role in synaptic plasticity and homeostatic processes and has garnered quite a bit of research in the therapeutics department. CBD and THC, which can both be extracted from cannabis, are chemically similar to the body’s natural endocannabinoids. Using forms of CBD, THC, and arachidonic acid-derived endocannabinoids, Anandamide (AEA) and 2-Arachidonylglycerol (2-AG) have shown to have neuroprotective effects and pain reduction. So how exactly does the endocannabinoid system do this?

What is the Endocannabinoid System?

https://www.frontiersin.org/articles/10.3389/fncel.2016.00294/full

As previously stated, AEA and 2-AG are two of the major endocannabinoids expressed within the body. These, along with CBD and THC, bind to the cannabinoid 1 receptor (CB1) receptor. The CB1 receptor is a G protein-coupled receptor located on presynaptic neurons and mediates the CNS effects of the endocannabinoids. AEA and 2-AG are produced by the enzymes diacylglycerol lipase (DAGL) and phospholipase D (PLD) and then activate the CB1 receptor, which regulates adenylate cyclase activity and inhibits cAMP, voltage-gated calcium channels, potassium channels, and neurotransmitter release. There is also the CB2 receptor, which is more concerned with the immune system as it is largely associated with inflammation and localized to microglia. AEA and 2-AG are agonists for the cannabinoid receptors and are triggered by an influx of calcium at postsynaptic sites after synaptic activity. The endocannabinoid system works to regulate a variety of events including pain perception, neuroprotection, learning, memory, and mood.

The Endocannabinoid System’s Role in Therapeutics

The use of endocannabinoids in therapeutics has increased greatly in the past few years with CBD pop-up stores and the legalization of marijuana in a handful of states. To read more on CBD for pain relief, read here: https://www.healthline.com/health/cbd-oil-for-pain#arthritis-pain-relief. The endocannabinoid system though has garnered quite a bit of attention in research by being linked to a variety of CNS diseases like Multiple Sclerosis, Alzheimer’s Disease, Huntington’s Disease, and Traumatic Brain Injuries (TBIs). In TBIs specifically, it’s been found that the endocannabinoid 2-AG and endothelin (ET-1) induced vasoconstriction, which constricts blood vessels and lessens blood flow) both form after a TBI. The balance of the two is what determines how bad in jury may be.

2-AG activates the CB1, CB2, and TRPV1 receptors to counteract the ET-1 response and dilates the blood vessels, decreasing the injury severity. This means that the endocannabinoid system is exerting a neuroprotective effect and has also been shown to lower the expression of proinflammatory cytokines in the early stages of a TBI, lowering the severity of the injury in the long haul. You can read more on the effects of the endocannabinoid system and TBI here: https://link.springer.com/article/10.1007/s12035-007-8008-6

Increasing endocannabinoids by injecting synthetic 2-AG or AEA to relieve pain and decrease disease/injury severity still requires more research but is looking to be a promising avenue in therapeutics. Currently, use of CBD and THC derivatives in different treatment forms, whether it be gummies, pills, or smoking, all seem to be beneficial ways to relieve pain, especially chronic forms. Hopefully research will continue on the use of endocannabinoid system’s role in neuroprotection and pain perception to increase the therapy for these disorders and pain management options.

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Endocannabinoids and Alzheimer’s Disease

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If you’ve done any research on the neurochemistry of Alzheimer’s Disease (AD), you’ve probably run into a few of the same molecular players like β-amyloid plaques and tau tangles that are present in the disorder. However, despite promising strides in AD research, fundamental questions about the disease still remain unclear, like why these plaques and tangles form, causing AD to happen to certain people and not others, or how best to treat the disease. Recently, a new player in the development of AD has been discovered: the endocannabinoid system. Let’s take a look at what this system is and how preliminary research has implicated its role in AD.

The Endocannabinoid System

The endocannabinoid system (ECS) involves several receptors and ligands (molecules that bind to receptors) in the brain. The CB1 and CB2 receptors are the most prevalent in this system. Both are G-protein coupled receptors (GPCRs), meaning that when the ligand binds, G-proteins associated with the receptors are activated. There are two categories of ligands for these receptors: endogenous endocannabinoids (those that are naturally produced in the brain) and exogenous cannabinoids (external ones that have been ingested, like cannabis). We will be focusing on the endogenous system for this post. The two main endogenous ligands in the ECS are the molecules AEA and 2-AG.

The ECS has a unique modulatory function in the brain because, once activated, it affects the presynaptic neuron. The synapse is the space between neurons (brain cells). Typically, signals are released from presynaptic neurons in the form of neurotransmitters that cross the synapse and serve as ligands for receptors on the postsynaptic neuron. However, the endocannabinoid system signals in the opposite direction in a phenomenon known as retrograde signaling. Activated CB1 and CB2 receptors cause a signaling cascade that releases neurotransmitter from the postsynaptic neuron that travels back to the presynaptic neuron. These signals then modulate the presynaptic neuron’s signaling, which allows the ECS to have broad effects on all signaling done by the presynaptic neuron.

Endocannabinoid signaling helps mediate synaptic plasticity, the ability of a synapse to change in response to signaling activity, which is an important process in learning and memory. The ECS is also important in pain perception, mood regulation, as well as in protection from neurodegeneration and in reducing inflammation in the brain.

Role of ECS in Alzheimer’s Disease

Because the endocannabinoid system assists with memory, reduction of inflammation, and protection from neurodegeneration, it makes sense that dysregulation of the system could play a role in Alzheimer’s Disease. Evidence also supports a role of the system: levels of key molecules are off in AD brains and CB1 and CB2 receptors are correlated with tau tangles and other hallmarks of AD.

Unfortunately, because much about AD remains unknown and researchers still lack a holistic animal model (laboratory animals modified to simulate a disorder; for example, mice whose genome has been edited to cause an autism-like state) for the disorder, few conclusions have been reached about the role of the ECS. Let’s take a look at cursory research that has been done.

  • The role of the ECS in AD seems to be similar its role in other neurodegenerative diseases about which more is known, like MS. In these disorders, the role of the endogenous system counteracts the “neurochemical and inflammatory consequences of β-amyloid-induced tau protein hyperactivity”. This means that the ECS protects the brain from negative effects of tau tangles in the brain that lead to development of AD.
  • As mentioned above, different levels of key molecules in the ECS have been found in AD brains.
    • In AD, there is an elevated number of CB2 receptors in the hippocampus. This is correlated with amyloid plaque, tau tangle levels, and levels of activated microglia (other brain cells that act on neurons).
    • There is reduced methylation (addition of meythl groups that prevent a gene from being transcribed and expressed) at the FAAH gene locus in AD. This leads to reduced levels of AEA in temporal and mid-frontal cortex in AD brains, an important ligand in the ECS.
    • 2-AG. the other major endogenous endocannabinoid ligand, exists at a potentially elevated level in AD.

Since research is still in its preliminary stages, a clear picture of the role of the ECS in AD remains evasive. Research is contradictory about points as basic as whether ECS signaling is overactive or underactive in AD brains. However, the ECS remains a promising route for future AD research, and CB receptor agonists like exogenous cannabinoids such as CBD have been proposed as potential treatments for AD.

Disease

The Universal Therapeutic Target’s New Competition: Huntington’s Disease

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Let us take a quick look at what the endocannabinoid system actually is. There are two major endocannabinoids in the body, specifically the brain: Anandamide (AEA) and 2-Aracidonoglycerol (2-AG). These molecules are considered to be lipophilic signaling molecule which can be released into the CNS via intracellular Ca2+ levels increasing or activation of metabotropic receptors. When endocannabinoid molecules are released into the post synapse of the neuron, it will activate the CB1 receptor as well as other GPCRs. The CB1 receptor is considered to target motor activity, appetite, immune cells, short-term memory, and pain perception. However, there is another receptor, the CB2 receptor, that is activated in a similar manner. This receptor is more associated with the peripheral nervous system and the immune system. The CB2 receptor targets areas, such as the kidneys, liver, eyes, gut, skin, reproductive system, and the cardiovascular system. Once these receptors have activated their appropriate cascade, then the endocannabinoid may be broken down via hydrolytic bond cleavage or by enzyme breakdown. Enzymes that help break down AEA and 2-AG include lipoxygenases and cytochrome P450.

Looking from the above mechanism, it seems that endocannabinoids play a relatively large role in everyday functioning. In terms of pain perception, activation of the endocannabinoid system helps to inhibit the pain cascade and can mitigate pain symptoms. Other studies have begun looking at using the activation of CB1 to increase appetite and combat certain eating disorders. Activation of the endocannabinoid system can sometimes mean using an exogenous source, such as ingesting marijuana in some manner. CBD is a naturally producing chemical in the body, and it is the influx that begins to show therapeutic treatment. However, the efficacy and ethicality of medical uses of marijuana is a conversation for another blog post.

One disease however seems to defy the beneficial therapeutics of medical intervention of the endocannabinoid system. Huntington’s Disease (HD) is a genetic mutation of the IT-15 gene causing an abnormal number of nucleotide repeats. These nucleotide repeats, often called polyglutamine (PolyQ) stretches can promote cell death and aggregation. When these PolyQ stretches continue to grow in size, the more likely the stretch to form a beta sheet. When a beta sheet is formed, chaperone proteins label it as misfolded and cause aggregation, which can be cytotoxic in nature. Early symptoms of HD include stumbling, difficulty concentrating, depression, and memory lapses. Further progression of the disease can lead to severe motor dysfunction, such as fidgety movements, trouble breathing, difficulty speaking, and/or trouble swallowing.

There is little to no possible therapeutics for HD at the moment, slightly due to the unknown diversity in size and cytotoxicity levels of the aggregates. One study by Xi et al. (2016) did examine activating CB1 receptors to alleviate symptoms. They noticed a decrease in HD-induced cell death, but the total number of aggregates increased significantly. This was also seen for increasing cAMP. However, another study by Xie et al. (2010) showed that forced influx of BDNF in the striatum has been shown to prevent cell death and prevent some of the motor dysfunction symptoms.  It was also shown to reverse decreased dendritic spine density and decrease abnormal spine morphology commonly seen in HD.

In conclusion, maybe Huntington’s can not be treated via the endocannabinoid system, but there are promising outcomes if CB1 receptors are activated. If the nature of the HD aggregates could be made soluble, then CB1 activation could be used as a therapeutic intervention in conjunction with other therapeutics.

 

Photo Sourced From: https://www.science.org.au/curious/people-medicine/huntingtons-disease

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Is Fat Bad? Exploring the Ketogenic Diet and Obesity

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One thing’s for certain in the world of nutrition and food lifestyle, it’s complicated. There are myriad, wildly different diets, many claiming fantastic results if you “just buy their product” that may or may not offer any clinical evidence to support their claims. In order not to be another flashy voice “selling a product” I aim to briefly cover the ketogenic diet, how it changes brain chemistry, and what this may mean for obesity and other health concerns.

First, what is the ketogenic diet?

http://perfectketo.com/wp-content/uploads/2017/03/Screen-Shot-2017-04-12-at-12.05.02-PM.png

Distinct from the typical U.S.A high carb diet, the ketogenic diet is high-fat and low carb, which shifts the body from using carbohydrates as the primary fuel to using ketone bodies as fuel source #1. You might be asking, what are ketone bodies? Ketone bodies are small intermediates in fat metabolism that can be used by the brain as an energy source! Historically, the keto diet has been used as an epilepsy treatment (for about a century) and is experiencing a medical renaissance, being looked at as a treatment for Alzheimer’s Disease, Multiple Sclerosis, Cancer, Parkinson’s Disease, and Autism Spectrum Disorder!

With so much work being done across various diseases, key questions are how does the ketogenic diet impact brain chemistry, and (for our purposes) how these changes might be useful in the context of obesity.

The ketogenic diet has been shown to 1) reduce hunger and 2) increase fatty acid oxidative metabolism—which both converge to overall decreases in body fat. This intuitively makes sense; if I’m less hungry and eating fewer calories while also burning more fat (and burning it more efficiently) I’m going to lose fat mass compared to my baseline.

What is sometimes harder to grasp is how eating fat can decrease fat—doesn’t fat make people fat? The trick is, in the context of the ketogenic diet, because carb intake is so low the body shifts into ketosis—where fats are the primary source of energy, not carbs. Typically, the brain loves sugar (glucose) as the preferred energy source. So when I eat a high-fat, high-carb diet the carbs are immediately metabolized into energy while the denser, more energy-rich fats are sent to storage in adipocytes (fat cells). When we were hunter/gatherers this made sense, store as much energy as possible because who knows when the next meal will come. In today’s hyper-modern world where those not experiencing food insecurity have easy access to cheap, calorie-dense food (think fast food), the body consuming many more calories than it can burn and stores the energy as fat.

This means that while in ketosis, I don’t have access to any glucose, therefore fats are the next most readily available fuel. This is why people can live healthily and decrease body fat while eating a high-fat, low-carb diet.

https://1m8t7f33dnra3sfk6v2rjurs-wpengine.netdna-ssl.com/wp-content/uploads/2018/05/Keto-Health-Benefits_BlogPhoto_R-1200×900.png

The ketogenic diet does not stop here, there are other neural consequences(think neuroinflammation) that come from removing carbs from the diet. First, scientific evidence has shown that a typical high-fat diet can trigger neuroinflammation by increasing pro-inflammatory cytokines (especially IL-1β and TNFα). These cytokines further trigger signaling cascades that result in insulin resistance, which dysregulates signaling pathways that make you feel “full”. This is bad news. Here’s the interesting thing though, other studies suggest that the ketogenic diet actually lowers neuroinflammation by decreasing concentrations of IL-1β and TNFα! What are we to make of this contradictory evidence?

https://onlinelibrary.wiley.com/doi/full/10.1111/epi.13038

One suggestion I have is that a high-fat diet, while harmful when coupled with high carbs, is beneficial in the context of a very low-carb lifestyle. Here’s the reason. The types of saturated fatty acids that trigger neuroinflammation only stick around too long in the bloodstream because the body is busy metabolizing glucose. During ketosis, those saturated fatty acids are more quickly broken down into ketone bodies, which are directly used by the brain and do not (to the best of my understanding) trigger neuroinflammation like saturated fatty acids.

The take-home messages are first, fats are not “evil”, they’re a fuel source—just like carbohydrates and protein. Second, the role of fats in health and disease ranges widely based on several factors, one of which is what other energy sources are available at a given time. Thirdly, the ketogenic diet has the potential for treating many diseases and as a key tool in situations of morbid obesity to increase fat oxidation. Finally, wrestling with both sides of the harmful/helpful fat debate illustrates that science can be controversial and that critical thinking skills are needed to make sense of contradictory evidence!

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Your Weight Is Completely Under Your Control: The Sneaky Myth Linking Obesity and Moral Failure

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Susan Greenhalgh’s 2015 book Fat Talk Nation: The Human Costs of America’s War on Fat, identifies the idea that “Weight is under individual control; virtually everyone can lose weight and keep it off through diet and exercise. Weight-loss treatments work; if they don’t, it’s due to lack of willpower on the part of the dieter,” as a key myth implicitly linking moral failure to obesity and underlying the burgeoning social, political, and economic effort to fight growing obesity rates in American citizens (30). Greenhalgh argues that this myth perpetuates and underpins many of the negative psychological and social consequences that people of a non-standard body size endure (31). Globally, 1.9 billion adults are overweight and, of these, 650 million were obese according to 2016 data from the World Health Organization. Therefore, the question of how and why obesity is linked to moral failure is highly relevant and has real consequences for many people. In fact, a 2012 study from the University of Minnesota found that 50% of people identifying as female and 38% of people identifying as male engage in unhealthy weight control behaviors. These harmful behaviors include things like skipping meals, fasting, smoking cigarettes, binge eating & purging, using laxatives or diuretics, and taking diet pills. Clearly, the link between obesity and moral failure has real, non-trivial consequences for individuals seeking a lower body size.

However, some key factors impacting your weight really aren’t subject to your conscious decision-making processes. Nothing in obesity makes sense except in light of dysregulated hormone balance. Let’s dive into the neuroscience behind hunger and obesity to explore how hormone balance in the hypothalamus regulates feelings of hunger and satiety.

Inside the Brain.

Ghrelin, Leptin, and Insulin are three key hormones that create the balance between hunger and satiety that tell your body when you need to eat, and when you’re feeling full. It’s complicated, so let’s use a graphic to break it down.

Fig 1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199695/

Ghrelin (not pictured on the graphic) signals to the brain that there is not enough available energy in the body and increases food intake by creating the feeling of hunger in the hypothalamus. Since Ghrelin and Leptin have opposite effects, it’s logical that they work through different mechanisms as well. Leptin (Fig 1: purple receptor, middle top of graphic) works in the opposite fashion by telling the brain that you have enough energy stored, creating feelings of satiety via a JAK-STAT signaling cascade. Insulin, like leptin, responds to energy stores but works in a slightly different way. Insulin will actually interact directly with the Leptin pathway via a protein signaling cascade that results in FOXO1 inhibition of STAT3, leading to satiety (Figure 1).

So how does this relate to the myth of control and the link between moral failure and obesity?

The balance between Leptin, Ghrelin, and Insulin is actually quite precarious. Any change in the relative levels of these hormones can lead to decreased feelings of satiety, increased eating, and obesity or, conversely, to increased feelings of satiety, decreased eating behavior, and symptoms of anorexia. Specifically, increased inflammation in the hypothalamus can lead to decreased leptin & insulin signaling, leading to increased eating and, potentially, obesity. So, clearly, every factor that forms an individual’s weight is not under their explicit, conscious control.

Conclusion

The vast majority of messages people receive surrounding weight and body size either explicitly or implicitly punish fat people. Greenhalgh identifies both critical (“if you don’t stop eating, you’ll look like that fat person”) and, often well-intentioned, complimentary examples (“Wow, you’ve lost weight; you look fantastic”) of what she calls “Biopedagogical fat-talk” as unnecessary and harmful to people’s self-conception and body image (35). Therefore, be kind to others and yourself, and remove comments about body size and appearance from your dialogues. Instead, seek a deeper connection in your conversations and move the focus away from appearances.

 

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Obesity and the Brain; What’s the Connection?

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Obesity and cognitive decline; how closely related could they be really?  As it turns out, the connection between these two can be mediated by one step.  Insulin Resistance.    A high fat diet leads to an increase in meta-inflammation, and if this inflammation becomes chronic, we see the development of Insulin Resistance, then ultimately Type 2 Diabetes.  Now certainly obesity and diabetes are no small factors in one’s life.  But what if I told you that’s not where it stops?  The insulin resistance caused from a fatty diet and/or obesity, is also believed to be a major underlying cause of Alzheimer’s disease.  Researchers have shown that obesity nearly doubles the risk of Alzheimer’s disease in later life, and even if remaining healthy, obesity has been related to an increase in risk of Mild Cognitive Impairment, regardless of age. These findings have also been recreated in animal models.

Now when you think of insulin, I’m sure most people will think of the same things, diabetes, blood sugar, released by the pancreas.  Now take a look at this figure.

At a cellular level, insulin does so much more than just that!  Even outside of AD specifically, researchers have shown that those with an increased BMI, and type 2 diabetes, had more atrophy in the frontal, temporal, and subcortical parts of the brain, which are all typically associated with learning and memory.  The reasoning behind the obesity/insulin resistance connection, is that obesity and it’s increase in adipose tissue results in a low level metabolic inflammation. This inflammation releases cytokines, and by looking at the figure below, you will see that the products of these inflammatory cytokines binding, actually inhibits the actions of insulin and insulin binding.

Finally, moving into Alzheimer’s and Dementia.  Studies have shown that elderly people with morbid obesity had a higher level of hippocampal markers that are associated with β-amyloid

Plaques, as well as tau protein accumulations, along with a decreased hippocampal volume.  The hippocampus is important in the formation of long-term memories, and between the appearance of plaques, and neurofibrillary tau tangles, along with a decrease in the hippocampus itself, we see the building blocks of AD.  For so long, when looking at obesity it was always “heart health” and that was the major focus, I think it now may be important to reference the risks associated with the mental well-being of individuals as well.  On the flip-side, It should be noted that not all obesity’s are made the same.  The major difference is metabolically healthy, vs unhealthy.  Metabolically unhealthy, means insulin pathways have already been damaged, and changed (i.e. Type 2 Diabetes). This can be treated, but ultimately not cured.  Metabolically healthy means that although the diet has increased inflammation, and begun to exhibit somewhat insulin resistant effects, it is not ‘chronic’, and the insulin pathway is still ‘rescuable’.  That means that although it is problematic, if a proper diet, is instituted, and the person can get back to a healthy body composition, the long-lasting effects of this inflammation will be less serious, and they would no longer be within the realms of major obesity related risk factors.  As we learn more about the interrelation of these conditions, it is important to recognize the longer-reaching issues that they may present down the road.  I believe the more people know about the dangers they are presenting to their bodies, the better the chance they will take the necessary steps to maintain their bodies adequately.

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Alzheimers Disease – Initial Connections for Future Answers

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While we have made numerous advancements in the past few decades, there is likely much more we don’t know, let alone understand, about the human brain than what we do. The field of neuroscience was not well established until the 1960s, and though we have made exponential leaps in knowledge of the brain since then, new discoveries often expose more gaps in knowledge. As one neuroscientist, Tom Sudhof, MD, PHD, has put it, “we are still in need of an understanding of the fundamentals” in order to understand elusive phenomena such as consciousness. “There is never a single discovery that changes science… science works as a process that extends over decades.”

A fundamental finding made in 1978 was the presence of insulin receptors in the brain, but it was not until the early 2000s that the role of insulin in the brain became a focus of research. In fact, the brain was classically thought to be insulin-insensitive (not affected by insulin), even after insulin receptors in the CNS were discovered. It’s fairly common knowledge that insulin plays an important role in PNS glucose regulation, but insulin is now understood to be involved in a wide variety of brain mechanisms as well, such as regulation of energy homeostasis in the brain, feeding behaviors, mood, and neuroprotection.

Another prominent role of insulin lies within learning and memory. These two phenomena within the brain are thought to be largely facilitated by a mechanism called synaptic plasticity, and insulin has been shown to interact with this process in a couple of different ways. Some studies have found that insulin can induce Long-Term Depression (LTD), which weakens synaptic strength based on its level of activity, through internalization of a type of glutamate receptors called AMPA receptors. Others show that administration of insulin enhances NMDA receptor glutamatergic transmission (associated with Long-Term Potentiation (LTP), which enhances synaptic strength also based on level of activity. These two components of synaptic plasticity have opposite effects, but they work together to process and store information in the brain. Which aspect insulin modulates may just depend on what subtype of receptor it interacts with.

When insulin in the body doesn’t function correctly, diabetes can result; when insulin signaling in the brain is impaired; several lines of evidence indicate that this may contribute to Alheimer’s disease. Interestingly, the two diseases may be connected, with Type 2 diabetes increasing risk for developing Alzheimer’s disease. As a brief overview, there are many ‘pieces to the puzzle’ for the etiology of Alzheimer’s, but they seem to all center around insulin resistance, which occurs when cells don’t respond properly to insulin. This insulin resistance, then, is hypothesized to be a significant contributor to not only diabetes, but Alzheimer’s as well, serving as a possible link between them.

The article Connecting Alzheimer’s disease to diabetes: Underlying mechanisms and potential therapeutic targets (2018) summarizes the many possible contributors to Alzheimer’s development. Three of these aspects are ABOs, gangliosides, and inflammation. ABOs are oligomers of the AB peptide, and function as toxins in the brain when they accumulate. When ABOs phosphorylate IRS-1, part of the insulin pathway needed for proper brain signaling, it becomes inhibited and the signal can’t be properly passed on.

Gangliosides also disrupt insulin signaling, but through different mechanisms than ABO’s. One way is by a type of ganglioside called GM3 disrupting interaction between the insulin receptor (IR) and cav-1, a protein that connects the IR with another substrate necessary for proper insulin signaling. The ganglioside GM1 may also promote insulin resistance by allowing ABO’s to bind to it, resulting in aggregation of these toxins into toxic amyloid structures. Finally, low grade yet chronic inflammation has been seen in brains with Alzheimer’s disease, suggesting that inflammation-mediating cellular pathways and the pro-inflammatory molecules they produce may be involved in Alzheimer development. 

We still don’t know exactly how all of these mechanisms fit together, but we are starting to find connections between them that explain how insulin resistance may arise. ABOs activate inflammation signaling, and gangliosides support production and clustering of ABOs, for example. In addition, Inflammation in the form of TNF-a production may perpetuate ABO development. On a broader scale, insulin resistance provides a key link between Alzheimer’s disease, Type 2 diabetes, and metabolic syndrome as well. Understanding this mechanism of pathogenesis does not make these diseases seem any less daunting or complex, but continuing research of and increasing awareness for different factors that contribute to insulin resistance  may help society take them more head-on. Perhaps, someday we might be able to prevent them from even occurring at all. 

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